Poly(ester amide)s with pendant azobenzenes: Multi-responsive self-immolative moieties for modulating polymer assemblies

Azobenzenes are well-known for their trans–cis photoisomerization, but it was recently demonstrated that azobenzene derivatives could also undergo reduction to trigger a 1,6-elimination and initiate de- polymerization of a self-immolative polymer. Herein we explore the optimization of azobenzenes as reduction-sensitive moieties, and their incorporation into functional materials. A library of azobenzenes with electron-withdrawing groups was synthesized, and their rates of reduction by hydrazine were deter- mined. Unexpectedly, a 2-Cl substituent increased the rate of reduction more than other electronegative or sterically-demanding substituents. Next, a new diester monomer containing the 2-Cl-azobenzene was synthesized and incorporated into a poly(ester amide) (PEA) backbone, which was then functionalized with PEO to afford an amphiphilic multi-responsive material. The photo- and reduction-sensitivity of the azobenzenes was then exploited to produce reversible and irreversible changes to the polymer nano- assemblies in water. Their responsiveness to light and/or hydrazine was studied by ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), and fluorescence spectroscopy of encapsulated nile red. Alternating irradiation with UV and visible light resulted in reversible trans–cis isomerization, which changed the polarity of the micelle core without disrupting the assemblies. Reduction by hydrazine resulted in the release of nile red from the micelle core, while residual assemblies were still detected by DLS, likely due to the presence of remaining hydrophobes. A combination of UV light and hydrazine resulted in the release of nile red and breakdown of the assemblies. These results suggest that the intrinsic responsiveness of azobenzene to both light and reductive stimuli can provide polymer assemblies that respond to one or more stimuli in unique and synergistic ways through a single multi-responsive unit

Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall

Pumping power as delivered by the heart is generated by the cells in the myocardial wall. In the present model study global left-ventricular pump function as expressed in terms of cavity pressure and volume is related to local wall tissue function as expressed in terms of myocardial fiber stress and strain. On the basis of earlier studies in our laboratory, it may be concluded that in the normal left ventricle muscle fiber stress and strain are homogeneously distributed. So, fiber stress and strain may be approximated by single values, being valid for the whole wall. When assuming rotational symmetry and homogeneity of mechanical load in the wall, the dimensionless ratio of muscle fiber stress (sigma f) to left-ventricular pressure (Plv) appears to depend mainly on the dimensionless ratio of cavity volume (Vlv) to wall volume (Vw) and is quite independent of other geometric parameters. A good (+/- 10%) and simple approximation of this relation is sigma f/Plv = 1 + 3 Vlv/Vw. Natural fiber strain is defined by ef = In (lf/lf,ref), where lf,ref indicates fiber length (lf) in a reference situation. Using the principle of conservation of energy for a change in ef, it holds delta ef = (1/3)delta In (1 + 3Vlv/Vw)

A model approach to the adaptation of cardiac structure by mechanical feedback in the environment of the cell

The uniformity of the mechanical load of the cardiac fibers in the wall is maintained by continuous remodeling. In this proposed model the myocyte changes direction in optimizing systolic sarcomere shortening. Early systolic stretch and contractility increases the mass of contractile proteins. Cyclic strain of the myocardial tissue diminishes passive stiffness, resulting in the control of ventricular end-diastolic volume. Utilizing these rules of remodeling in our mathematical model yields that the natural helical pathways of the myocardial fibers in the wall are formed automaticall

Effect of statins on venous thromboembolic events: a meta-analysis of published and unpublished evidence from randomised controlled trials

Background - It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins. Methods and Findings - We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Please see later in the article for the Editors' Summary. Conclusions - The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out

The year in cardiovascular medicine 2020: arrhythmias

Summary of the progress in arrhythmias in 2020. RACE4 and ALL-IN indicated that integrated nurse-led care improves outcomes in AF patients. The same was reported for early rhythm control therapy and cryoablation as initial AF treatment. Subcutaneous ICD was non-inferior to classical transvenous ICD therapy in PRAETORIAN. One mechanistic study showed that autoantibodies against misexpressed actin, keratin, and connexin-43 proteins create a blood-borne biomarker profile enhancing diagnosis of Brugada syndrome. Another mechanistic study indicated that transseptal LV pacing yields similar improvement in contractility as His bundle pacing whilst being more easy to execute. In PRE-DETERMINE a simple-to-use ECG risk score improved risk prediction in patients with ischemic heart disease possibly enhancing appropriate ICD therapy in high risk patients